tbuckley/cabot-search huggingface dataset:
P11.14.B PROGNOSTIC ASSOCIATIONS OF STEROID USE IN GLIOBLASTOMA: A POPULATION-BASED STUDY
Authors: Y Abdel Moneim, M Weller, D Gramatzki
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Steroids are widely used in brain tumor patients to control symptoms related to tumor and cerebral edema. A possible detrimental effect of steroid treatment on prognosis in glioblastoma patients has been proposed. Whether this represents only a negative patient selection due to the potential confounding factor of steroid treatment or whether glucocorticoid use per se causes a worse prognosis remains a matter of debate. MATERIAL AND METHODS We reviewed retrospective data of 225 patients diagnosed with isocitrate dehydrogenase (IDH)-wildtype glioblastoma from 2010 to 2014 in the Canton of Zurich, Switzerland. We assessed clinical data and the use of steroids at different time points. Survival data were analyzed with the Kaplan-Meier method, and corrections for known prognostic or predictive factors were performed with Cox regression analyses. Correlations were determined with Spearman’s correlation coefficient. RESULTS Most patients (N=203, 95%) received steroids at least once in the first year after diagnosis, the majority (N=153, 69%) in the perioperative setting (defined at the time of hospitalisation for the surgery plus/minus seven days), and 94 patients (62%) in the first three months. Steroid use at three months after surgery was associated with with steroid treatment at six months, too (p&amp;lt;0.01). The latter was associated with inferior overall survival after correction for known prognostic factors (p=0.006). CONCLUSION Use of steroids at six months after diagnosis was associated with inferior survival in glioblastoma even when controlling for confounding factors. The precise mode of action of steroids in this setting remains to be identified, but cytoprotective effects of tumor cells versus radiotherapy and chemotherapy as well as decreased immune function of the host are potential mechanisms.
P11.27.A RADIOTHERAPY-INDUCED CHANGES IN THE BRAIN: A LONGITUDINAL STUDY IN PATIENTS WITH LOW-GRADE GLIOMAS
Authors: K Wickborn, H L van der Weide, M C A Kramer, E F J de Vries, R J H Borra, J M Spikman, A M Buunk, C W J van der Weijden, A van der Hoorn
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Low-grade gliomas (LGG) are brain tumors with a comparably moderate malignancy grade and slow progression. Most patients are young to middle-aged adults with a relatively good prognosis given the advancement of multimodal treatment METHODS . Radiotherapy (RT) is an integral component of this treatment. During RT, protons or photons are used to eradicate the tumor while minimizing the damage to surrounding areas. However, healthy brain tissue is inevitably exposed to radiation, which can have adverse effects with a severe impact on the cognition and quality of life of survivors. With the improved survival of patients, understanding RT-induced changes and their consequences becomes more and more important. Here, we investigate the volumetric changes in LGG patients 2.5 years after treatment to gain insights into the neuronal long-term effects of RT. MATERIAL AND METHODS To quantify the volumetric changes in the brain of LGG patients over time, LGG patients (N= 17) were scanned before and 2.5 years after proton RT. For both time points, volume parameters per brain structure were extracted using T1w MRI scans and cNeuro® software. The volumes of the structures in the tumor-contralateral hemispheres before RT were compared with the measures 2.5 years after RT using paired samples t-tests or nonparametric alternatives. RESULTS Analysis of the total grey matter of the contralateral hemisphere indicated a statistically significant volumetric reduction in our cohort 2.5 years after RT. An analysis targeting volumetric changes in the contralateral hippocampus also indicated a statistically significant decrease. In the following steps, additional structures will be analyzed. CONCLUSION Preliminary results suggest a potential RT-induced decrease in the tumor-contralateral grey matter and hippocampal volume 2.5 years after treatment. Volumetric changes will be compared with the received radiation dose per structure using radiation dose distribution maps.
P13.17.B PREDICTING KI-67 PROLIFERATION INDEX OF MENINGIOMAS ON MRI: A DEEP LEARNING METHOD BASED ON MULTI-MODAL INFORMATION
Authors: C Chen, J Xu
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND A high Ki-67 index usually suggests accelerated cell proliferation of meningioma related to significant tumor growth as well as increased recurrent risk. This study aimed to explore the feasibility of deep learning method in predicting Ki-67 index of meningiomas with multi-modal information. MATERIAL AND METHODS Pre-treatment magnetic resonance images were retrospectively curated from 521 patients with surgically resected, pathologically confirmed meningiomas from three institutions. The cases were classified into low-expressed or high-expressed groups with a threshold of 5% of Ki-67 index. Predictive models were developed with multi-modal deep learning network by using traditional radiological findings, radiomics features extracted from tumors, and MRIs of meningiomas. The performance of the models was evaluated with area under curve (AUC), accuracy (ACC), sensitivity, and specificity. In addition, 127 cases with incidental small meningioma were recruited and followed up in 2 years, to investigate if the model could be used for predicting the tumor growth to assist in patient management. RESULTS Overall, 371 patients were enrolled for model development and primary analysis. The predictive model showed good performance with AUC of 0.798, ACC of 0.710, sensitivity of 0.613, and specificity of 0.806 in the internal test. It also achieved robustness in the external test cohort consisted of 150 cases, with AUC of 0.758, ACC of 0.661, sensitivity of 0.677, and specificity of 0.645. Moreover, model-predicted high Ki-67 tumor was associated with significant tumor volume growth happened in two years. CONCLUSION The predictive model can efficiently predict the Ki-67 index in meningioma patients, and showed good potential in facilitating the therapeutic decisions.
P07.13.B A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)
Authors: M S Ahluwalia, M McDermott, A Ozair, A A Khosla, A Sahgal, M Mishra, A Achrol, G Woodworth, N Lipsman
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The blood-brain barrier (BBB) limits the efficacy of systemic therapies for brain metastases (BM), for which non-small cell lung cancer (NSCLC) is the most common etiology. BBB disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) results in non-invasive BBBD synergistically with intravenously (IV) administered microbubble oscillators. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy. METHODS LIMITLESS is an ongoing prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in 2:1 ratio. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting measurable disease criteria as per response assessment in neuro-oncology for BM (RANO-BM). Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using a 220 kHz LIFU device with real-time acoustic feedback for maintaining effective cavitation. Pembrolizumab is infused immediately thereafter, and a repeat MRI is done 24-48 hours later to confirm the closure of BBB each cycle. The primary study endpoint is the overall objective response rate (ORR) at 6 months, as assessed using RANO-BM criteria. Using a Bayesian design for power analysis, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for a total sample size of N=96, 64 subjects in LIFU and 32 in the control arm, for 80% power using a two-sided chi-square test with an alpha of 0.05. For the upper-bound estimate ORR of 45% in the LIFU arm and 30% in the control arm, the study needs N=369 subjects; 246 in the LIFU arm and 123 in the control arm. The secondary outcomes are the best objective response rate and median time-to-response per treatment arm. The exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. RESULTS Patient enrollment commenced in 2022. CONCLUSION Findings from this trial will be critical to liquid biopsy in brain metastases (Clinical trial information: NCT05317858).
P20.01.A CLINICAL APPLICATION OF RELATIONSHIP BETWEEN GENETIC ALTERATION AND INTRAOPERATIVE FLUORESCENCE ACTIVITY OF 5-AMINOLEVULINIC ACID IN BRAIN METASTASIS OF NON-SMALL CELL LUNG CANCER
Authors: H Y Jeong, W J Seo, H G Kim, S H Kim, T M Nam, J H Jang, K H Kim, S H Kim, Y Z Kim
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Distant metastasis into major organ is a major cause of death in cancer patients. Especially, metastasis to brain is known to duplicate the mortality of cancer patients because brain metastasis makes patients neurologically independent in daily activities. Despite surgical resection of brain metastasis is a core strategy for management, it is not possible for all brain metastasis due to eloquent location, multiple lesions, or clinical condition of patient. With advancement of technology in brain tumor surgery, fluorescence image, such as 5-aminolevulinic acid (5-ALA), can help detect the residual tumor during surgery. Recently, genetic alteration of cancer is additionally considered as prognostic factor with being added into traditional prognostic system, such as GPA scoring system. The primary objective of this study is to examine the fluorescence patterns of 5-ALA in brain metastasis surgery and investigate the results of genetic alteration in brain metastasis using next generation sequencing technique. MATERIAL AND METHODS Medical records of patients with brain metastasis of non-small cell lung cancer at our center from January 2017 to June 2022. Among them, the patients who were treated with surgical resection under 5-ALA fluorescence image and had NGS results were included in the analysis. RESULTS Total 72 patients were eligible for analysis. Mean follow-up duration was 12.36 months. Recurrence occurred in 28 (38.9%) patients and 46 (63.9%) patients succumbed to NSCLC. Mean recurrence-free survival (RFS) was 14.57 months and mean overall survival (OS) was 16.29 months. Strong fluorescence was obtained in 56 (77.8%) patients during surgery. In the NGS data of brain metastasis, genetic alteration of cell cycle regulation, DNA repair, tumorigenesis, proliferation, epigenetic regulation, and cancer immunology were detected in 73.6%, 44.4%, 56.9%, 66.7%, 30.6%, and 2.8%, respectively. In multivariate analysis, KPS, RPA class, extent of resection, modality of adjuvant treatment, genetic alteration of cell cycle regulation and cellular proliferation were associated with RFS. Additionally, age, KPS, status of NSCLC, RPA class, GPA score, modality of adjuvant treatment, genetic alteration of cell cycle regulation and cellular proliferation were associated with OS. CONCLUSION The presenting study suggested that microscopic complete resection with assist of fluorescence image could improve clinical outcome, and strong fluorescence image could reflect the genetic alteration of cell cycle regulation and cellular proliferation which are poor prognostic factors.
P17.11.A DEVELOPMENT AND CHARACTERISATION OF THE QCELL-R RECURRENT GLIOBLASTOMA PRIMARY CELL LINE RESOURCE: MODELS TO DRIVE BREAKTHROUGH DISCOVERIES IN BRAIN CANCER
Authors: K A Bradbrook, U Baumgartner, F M Smith, R Johnston, L Harris, S Hoyte, Z Lwin, H Alexander, R Jeffree, B W Day
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive brain tumour in adults, with a median survival of only 15 months. Despite aggressive treatment with chemotherapy using temozolomide and radiotherapy, GBM has a high prevalence of recurrence with almost all cases recurring within the first year. This highlights a clear need to develop a deeper understanding of GBM recurrence and to develop effective models to test novel therapies. The vast inter- and intra-tumoural heterogeneity and tumour cell plasticity are complicating the development of effective therapies for brain cancer patients. Large-scale genomic analyses of primary and recurrent human GBM tumour samples have revealed a complex genomic architecture. However, the majority of GBM discovery science has been conducted in treatment naïve tumour models, which fail to capture therapy resistance and tumour evolution. Hence, these changes have been difficult to link to GBM growth and functional cell properties upon recurrence. MATERIAL AND METHODS To address this, we have developed the QCell-R resource, a collection of functional models of recurrent GBM. In collaboration with the Royal Brisbane and Women’s Hospital (RBWH), pair-matched patient tumour samples from the initial resection and at recurrence post-therapy have been collected. From these tissue specimens, in vitro cell lines in both 2D and 3D cultures and in vivo orthotopic xenograft models have been developed. Response to standard of care therapy (temozolomide and radiotherapy) were assessed using IncuCyte proliferation assays. Bulk mRNA, scRNA and exome sequencing were also performed. RESULTS QCell-R consists of 11 patient-derived recurrent GBM models, with the time between resections varying from 5-13 months. There are four pair-matched QCell-R models, as well as three standalone recurrent models. Response to standard of care therapy varied between models, with one model exhibiting a four fold higher growth rate-50 (GR50) after temozolomide treatment and a 2.7 fold increase in radiation resistance compared to the matched treatment naïve counterpart. The mRNA and scRNA sequencing has been compared to publicly available datasets to identify genes of interest that may be targetable in recurrence to test in these models. CONCLUSION QCell-R represents a valuable resource to define novel therapies for recurrent GBM. Elucidation of tumour heterogeneity and tumour evolution will identify targetable genes contributing to therapy resistance in these models. Identifying these targetable genes from QCell-R allows the development of novel treatments, creating strategies that may reduce the rate of recurrence by limiting therapy resistance and inhibiting recurrence-initiating cells.
P06.10.A CAR-ENGINEERED PRIMARY NK CELLS SHOW PROMISING EFFECTS AS TARGETED THERAPY AGAINST EGFR-POSITIVE GLIOBLASTOMA
Authors: B Roller, L M Reindl, F Strassheimer, G Ludmirski, P Elleringmann, A Kiefer, J Röder, J P Steinbach, W S Wels, E Ullrich, M C Burger
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GB) is the most frequent primary brain tumor and despite intensive treatment regimens including surgery, radiotherapy, and chemotherapy, it is still characterized by a dismal prognosis. Immunotherapies such as T cells or natural killer cells (NK) that carry tumor-specific chimeric antigen receptors (CAR) hold promise for the development of more effective treatment strategies. CAR-engineered derivatives of the human NK cell line NK-92 targeting EGFR or EGFRvIII showed potent antitumor activity against glioblastoma cell lines in vitro and in vivo. Nevertheless, NK-92 has some limitations compared to primary NK cells, such as the required irradiation prior to application in humans. MATERIAL AND METHODS To overcome this limitation, we evaluated the suitability of peripheral blood derived human primary NK cells (pNK) as carriers for a CAR targeting the common GB antigen epidermal growth factor receptor (EGFR) and the tumor-specific EGFR variant EGFRvIII. pNK cells from healthy donors were transduced with a lentiviral vector encoding the cetuximab-derived 225.28.z CAR (CAR-pNK) which recognizes an epitope common to both receptors. Specific tumor cell lysis by the CAR-pNK cells was then investigated in FACS-based cytotoxicity assays with GB cells expressing EGFR, EGFRvIII, or both target antigens. In addition, we tested in vivo feasibility of the CAR-pNK cells by single time intravenous injection in a subcutanous LNT-229/EGFRvIII glioblastoma xenograft model. RESULTS In comparison to non-transduced pNK cells, CAR-pNK cells displayed enhanced lysis of LNT-229 GB cells expressing EGFR and EGFRvIII. Likewise, markedly increased cytotoxicity of CAR-pNK was observed against GB cell lines such as SKMG-3 and BS153 with intrinsic EGFR gene amplification or expression of EGFRvIII, respectively. Furthermore, in a subcutaneous LNT-229/EGFRvIII glioblastoma xenograft model we observed delayed tumor growth after a single intravenous injection of CAR-pNK cells. CONCLUSION In summary, these results demonstrate promising efficacy of primary CAR-NK cells targeting EGFR and EGFRvIII both in vitro and in vivo. In ongoing work we are evaluating CAR-pNK cells in an orthotopic LNT-229 glioblastoma xenograft mouse model, which may provide the basis to translate this approach to early clinical testing.
P12.05.B THE ROLE OF ONCO-METABOLITE IN THE IDH MUTANT GLIOBLASTOMA MICROENVIRONMENT
Authors: S Behringer, K Joseph, J Beck, O Schnell, H Heiland, V M Ravi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Recently, we found that the reactive astrocytes in the IDH wild type glioblastoma contribute to anti-tumor immunity and support pro-oncogenic signaling. Here, we characterized the transcriptomic signature of IDH1/2-mutant glioma associated astrocytes and determined a unique inflammatory transformation, profoundly different to astrocytes in IDH wildtype glioma patients due to an onco-metabolite R-2-hydroxyglutarate using Next generation sequencing and human ex-vivo slice model. MATERIAL AND METHODS We purified and transcriptionally profiled astrocytes from 9 patients with confirmed IDH1-R132H mutation, by means of RNA-sequencing and the data were analyzed using the established pipelines. We also used spatial transcriptomics to evidently show the spatial distribution of astrocytes in IDH-mutated/wildtype glioma samples. We validated our findings using human organotypic slice model inoculated with IDH-mutant cell line or treated with oncometabolite 2-hydroxy glutarate. Additionally, LC-MS was further used to give us a chart of neurotransmitters due to altered microenvironment. RESULTS Our results from RNA sequencing showed a transcriptional transformation of reactive astrocytes within the microenvironment of IDH-mutated tumors compared to wildtype glioma by means of RNA-sequencing of purified astrocytes. And, using our established human neocortical GBM model inoculated with IDH mutant tumor and R-2HG treatment, we showed that we were able to activate inflammatory transcriptional programs in astrocytes, mediated by the presence of microglia. Further, by spatially mapping the transcriptomic profiles of purified microglia, we were able to confirm that microglia also demonstrate inflammatory activation in IDH mutated glioma. This inflammatory astrocyte transformation is associated with a loss of neurotransmitter homeostasis (disrupted levels of glutamate) in the treated sections, as has been previously reported in IDH mutated tumors. Additionally, R-H2G increased neuronal spiking rate in, pointing to potential excitotoxicity. CONCLUSION Our work provides a crucial contribution towards understanding the role of R-2HG in the IDH mutant glioma microenvironment and sheds light on the significant microenvironmental differences to IDH wild-type glioma.
P11.35.B STEREOTACTIC RADIOTHERAPY FOR VESTIBULAR SCHWANOMMAS: THE WESSEX EXPERIENCE
Authors: S Main, H Yeo, L Caamina, J Ching, J Kaylan, G Sinclair, R Shanmugasundaram, E Clarke
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Review of SRT for vestibular schwannoma (VS) within Wessex region led by University Hospital Southampton (UHS). UHS treat tumour volumes max 2.5cm in diameter without brainstem compression with 21Gy/3#. We reviewed the experience of local control and toxicity profile in our centre comparing with 1 and 5 fraction SRT schedules. We present three fraction SRT as an appropriate fractionation schedule. MATERIAL AND METHODS This is a retrospective analysis of patients treated for radiologically diagnosed vestibular schwannoma from 2019 to present. Patient notes, audiograms, imaging and radiotherapy planning system were reviewed for data collection. No patients were removed from analysis due to missing data. RESULTS 84 patients have been treated with SRT for VS. Median age 66 (39-94). 12Gy/1# (1#) in 36 patients, 21Gy/3# (3#) in 36 patients, 25Gy/5# (5#) in 12 patients. In the 1# group PTV volume 0.31cm3-4.44cm3 (median 1.12cm3), in the 3# group PTV volume from 1.03cm3 to 5.52cm3 (median 2.37cm3), in the 5# group 2.05cm3-5.44cm3 (median 4.12cm3). All patients have radiologically stable disease to date. Objective radiological response noted in 14 patients (38.9%) in 3# group this is higher than any other group and statistically significant (p=0.016). Pre-treatment serviceable hearing only in a minority of patients. Treatment related toxicity was seen in 27% in the 1# group, 19% of patients within the 3# group, and 33% in the 5# group. This was mostly mild and self-limiting. Facial nerve toxicity was seen in 8.3% of the 1# group, 16.7% of 3# group, and 33.3% of the 5# group. However, this was only persistent in 2 patients in 1# group (5.6%), 2 patients in the 3# group (5.6%), and 1 (8.3%) in the 5# group. There is no statistical difference in toxicity between any group using Chi squared test. In 3# group, when Dmax limited to &amp;lt;26Gy (n=15), the frequency of facial nerve toxicity reduces to 1 (2.78%). CONCLUSION Three fraction SRT provides excellent local control with high levels of objective radiological response in tumours up to 4cm3, however, long term follow-up is required. This treatment has acceptable toxicity which is not significantly different from alternative fractionation schedules and is improved by limiting Dmax to &amp;lt;26Gy.